Summary of Work: Neurodegenerative diseases pose an increasing challenge to public health as the population ages. Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease of the motor system. Its etiology is essentially unknown, but exposure to environmental neurotoxins may play a role. We conducted a case-control study of ALS to investigate the effects of cumulative lifetime exposure to lead and other neurotoxins, including mercury, solvents, and pesticides. Field work is complete; 110 ALS cases, 31 clinic controls, and 270 population controls were enrolled in the study. We assessed lead exposure in three ways: we measured bone lead using x-ray fluorescence, an innovative noninvasive technique; we measured blood lead; and we administered a structured in-person interview to gather information on potential occupational, residential, and lifestyle sources of exposure. Results to date show that ALS is strongly associated with both blood and bone lead levels. The relationship with blood lead was unexpected and suggests that metabolism of bone lead may be different in ALS patients. ALS was also associated with occupational exposure to lead, but not with residential or recreational exposures. Overall, these results extend previous studies to suggest that lead exposure is a risk factor for ALS. We also found that ALS was associated with cigarette smoking. Further analyses will explore the relationship of ALS to other neurotoxic exposures and to dietary antioxidants. In addition, the relationship of ALS to a common polymorphism in the gene for delta-aminolevulinic acid dehydratase will be studied to explore further the potential relationship between ALS and lead metabolism.